Treatment of NASH has relied of lifestyle changes, but a new medication offers the first targeted therapy for the disease.
Given the high degree of association between obesity and non-alcoholic steatohepatitis (NASH), the cornerstone of treatment has been weight loss and exercise. Weight loss of just 3% to 5% can reduce fat in the liver and loss of 10% or more of body weight resolves NASH in 90% of patients with 45% seeing fibrosis regression.[1]
Another aspect of diet may also reduce the risk of NASH and development of fibrosis – coffee. A meta-analysis found that drinking two or more cups of caffeinated coffee reduced the relative risk of liver fibrosis in individuals with non-alcoholic fatty liver disease (NAFLD) by 32%.[2]
New pharmacotherapy approved
In March 2024, the U.S. FDA approved the first pharmacotherapy for patients with NASH and stage 2 or 3 fibrosis, the patients at most risk of cirrhosis and hepatocellular carcinoma as well as liver-related and all-cause mortality.
“Previously, patients with NASH who also have notable liver scarring did not have a medication that could directly address their liver damage,” said Nikolay Nikolov, M.D., acting director of the Office of Immunology and Inflammation in the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Rezdiffra will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.”[3]
Rezdiffra (resmetirom) acts as a partial activator of a thyroid hormone receptor beta agonist that reduces fat in the liver. As thyroid hormones regulate liver lipid metabolism, resmetirom’s activation of this thyroid hormone receptor reduces fat in the liver.[4] In the pivotal trial, up to 29.9% of participants treated with resmitirom achieved NASH resolution and no increase in liver scarring and up to 28% of the resmetirom-treated participants saw a reduction in liver scarring and no worsening of NASH.[5]
Emerging and repurposed therapies
Several medications for diabetes also improve NASH, but fewer appear to reduce fibrosis. These include pioglitazone, a thiazolidinedione, and glucagon-like peptide 1 (GLP-1) receptor agonists.
Over a three-year period, 58% of trial participants who took 45 mg of pioglitazone per day in combination with a 500 kcal per day deficit diet achieved a two-point drop in their non-alcoholic fatty liver disease activity score in two histologic categories and 51% resolved NASH entirely compared to 19% of those randomized to diet only. Pioglitazone also reduced mean fibrosis scores, but this was not statistically significantly. Fewer patients demonstrated fibrosis progression compared to placebo, 12% vs 28%, respectively, (p=0.039).[6] Pioglitazone can cause or worsen heart failure, lead to weight gain, accelerate loss of bone density, damage the liver and increase the risk of bladder cancer.[7]
While semaglutide did not demonstrate improvement in fibrosis in patients with NASH in a 48-week phase 2 trial,[8] two other GLP-1 receptor agonists have shown positive results.
A phase 2 trial of tirzepatide that enrolled 190 participants with biopsy-confirmed NASH and stage 2 or 3 fibrosis found that 44% to 62%, depending on dose, of those receiving tirzepatide achieved resolution of NASH without worsening of fibrosis compared to 10% of those receiving placebo at 52 weeks. Between 51% and 55% of those in the tirzepatide group saw a one stage or better improvement in fibrosis without worsening of NASH versus 30% in the placebo group.[9]
Retatrutide, a novel triple agonist of GLP-1, glucagon receptors and glucose-depended insulinotropic polypeptide, has recently shown outstanding results in resolving NAFLD, with 86% of participants achieving less than 5% liver fat in 24 weeks. Whether retatrutide will also reduce fibrosis remains to be determined, however.[10]
Pegozafermin, a long-acting glycopegylated fibroblast growth factor analogue, has also shown some effectiveness in reduction of fibrosis in patients with NASH and stage 2 or 3 fibrosis. A phase 2b trial found that fibrosis improved by one stage or more in 22% to 27%, (depending on dose) of participants who received pegozafermin once every two weeks for 24 weeks compared to 7% in the placebo group. NASH resolved in 23% to 37% of the pegozafermin group and 2% of the placebo group.[11].
